The role of mechanical cues in biological systems: from tissue micromechanics to immune cell motility
Embargo Date
2026-06-08
OA Version
Citation
Abstract
Mechanics play a vital role in health and disease: mechanical cues dictate processes in cellular activity and signaling, define tissue response and behavior, and influence disease response and progression. Altering normal mechanics can therefore have wide-reaching biological, functional, and immunological implications, and understanding mechanics and its relationship to biological function is of crucial importance. In this dissertation, we investigate biological mechanics from three distinct perspectives. First, we describe the development and application of the μElastography platform: a novel platform that enables high-resolution mapping of tissue elasticity in 3D in intact samples. This platform is compatible with biological samples from the cellular to the organ scale, allowing for the detection and mapping of internal mechanical heterogeneities in 3D that traditional stiffness measurement techniques typically fail to detect. We apply the μElastography platform to map the internal elasticity distributions of hydrogel samples, multicellular cancer spheroids, and intact murine lymph nodes. Second, we probe how the micromechanics of the intact, functional lung evolve across the murine lifespan at the alveolar and capillary scales. Leveraging the crystal ribcage, we vary transpulmonary and vascular pressures across the lung and find age-related increases in alveolar and vascular distensibility that correspond to decreasing Young’s modulus of the tissue. We additionally probe the mechanical and functional differences between positive-pressure (as in mechanical ventilation) and negative-pressure (as in spontaneous breathing) ventilation modes, with significant differences in vascular distensibility emerging between the pressure types. Third, we examine immune cell motility in the altered mechanical microenvironments of metastatic melanoma. Typical methods for quantifying immune response rely on histology or 2D in vitro assays and fail to capture the spatiotemporal dynamics of the cells’ migratory and killing activity in situ. We overcome these limitations by using the crystal ribcage in conjunction with in vivo labeling of the mouse’s native CD8+ T cells in order to image actively migrating CD8+ T cells in the functional lung. We examine the role of tumor size-dependency on T cell motility and probe additional mechanical parameters such as the role of the mechanosensitive YAP pathway and the tidal (respiratory) volume of the lung. We find that poorly immunogenic tumors have decreased CD8+ T cell infiltration and motility compared to highly immunogenic tumors, whose enhanced CD8+ T cell motility extends beyond the boundaries of the tumor into the peritumor: a physically and immunologically unique and understudied region. These motility signatures hold valuable implications for developing and evaluating therapeutic approaches. Taken together, these three projects underscore the critical role of mechanical cues in shaping biological function, offering new perspectives on how tissue mechanics influence disease progression and immune cell behavior in complex, physiologically relevant environments.
Description
2025
License
Attribution 4.0 International